Most of the population of all age groups shows inadequate levels of vitamin D both in developing and industrialized countries. The elderly population is among the high risk groups because of its frequent comorbidities, little sun exposure and poor dietary intake of vitamin D. The signs and symptoms of vitamin D deficiency may be unclear and nonspecific, therefore a proper supplementation not only can prevent childhood rickets and fractures in old age, but may also have a protective effect against the risk and consequences of falls, and probably against several chronic degenerative diseases as well. Starting from the examination of medical literature data, the authors discuss the benefits of a proper supplementation of vitamin D at different stages of life.

The term “vitamin D” refers to a group of fat-soluble hormones with specific biological effects, endocrine effects on calcium-phosphorous metabolism, and autocrine and paracrine effects on several other systems. Vitamin D2 (ergocalciferol), which originates from ergosterol and can be found in the plant kingdom, and vitamin D3 (cholecalciferol), which is largely synthesized in the skin through ultraviolet rays or taken with certain food (such as fat fish, cod liver oil, eggs and butter), are especially relevant. Since vitamin D is highly liposoluble, it is stocked in the body fat in order to be used also in winter.

The active form of vitamin D3 can be obtained through two different cholecalciferol hydroxylation reactions: the first, in the liver, with the development of 25 OH vitamin D3 (calcidol), and the second, in the kidney, with the development of 1,25 OH2 vitamin D3 (calcitriol) (Fig.1). Ergocalciferol can be subjected to similar hydroxylation reactions. Active metabolites reach target tissues through blood, and here they bind to a specific nuclear receptor protein (Vitamin D Receptor or VDR) (Attachment 1).

The endocrines effects of vitamin D, which are determined by the 5% of the amount present in the body, can occur:

1) In the intestine, where the synthesis of the calcium-binder protein, which helps its absorption in the duodenum, is stimulated.

2) In the bone, where the increasing of the osteoblastic activity and mineralization are stimulated.

3) In the parathyroid, where vitamin D inhibits the parathyroid hormone sythesis (PTH) both directly, blocking the gene transcription, and indirectly, by increasing the ionized calcium plasmatic levels.

Still not completely known, the autocrine and paracrine effects involve about 85% of vitamin D and have been detected in many tissues, where vitamin D also helps the mechanisms of cell proliferation and differentiation and in the immune-modulating mechanisms.

Furthermore, the VDR presence in the placenta suggests that calcitriol is able to function as a autocrine/paracrine regulator between mother and fetus, letting the trophoblasts pass without an immune response of the mother and so helping the implantation of the embryo in the uterine mucosa.

Causes of hypovitaminosis D

Sun exposure should provide a sufficient synthesis of vitamin D, but such an exposure is influenced by latitude, seasons, the use of barrier creams and pigmentation of the skin (dark-skinned people need a greater sun exposure to get an adequate synthesis of vitamin D).

Over the last years a severe and widespread prevalence of hypoitaminosis D has been documented worldwide, possibly related to changes in behaviour. In fact the deficiency of vitamin D is most frequently a consequence of insufficient sun exposure or, very seldom, of a poor dietary intake of vitamin D. Being among the countries which are situated in the “vitamin D winter area” (lat. 37° North), Italy is considered at risk for hypovitaminosis D in winter, when the organism cannot synthesize sufficient amount of vitamin D3 (Attachment 2).

In addition, vitamin D deficiency can be due to the chronic ingestion of steroids or antiepileptic medications and to diseases that cause intestinal malabsorption (such as celiac disease, IBD, pancreatic insufficiency, hepatic cholestasis, previous gastrectomy).

The overt and subclinical deficiency of vitamin D is common at any age but it mainly affect child development stages, dark-skinned people, the elderly, institutionalized or underfed individuals, and chronic disease carriers (especially diseases of the kidney and the liver where vitamin D is activated).

Reserves decrease in the elderly due to both the reduced synthetic capacity of the skin and less cutaneous sun exposure.

Diagnosis of Hypovitaminosis D

In each individual the availability of an adequate supplies of vitamin D can be evaluated through the quantity of 25 OH vitamin D3 in the serum, which should be between 30 and 70 ng/ml for optimal skeletal and extraskeletal health. Values between 20 and 30 ng/ml are considered insufficient, while concentrations under 20 ng/ml are a clear deficit (Tab.1).

Serum 25 OH vitamin D3 concentrations can also be used as indicators of the nutritional status in pregnant women. Although there has been no general consensus on the optimal level of vitamin D intake so far, the American Academy of Pediatrics (AAP) recommends to evaluate serum vitamin D levels from the early stages of pregnancy.

The “Agenda della Gravidanza” of Piedmont does not currently provide the screening of every pregnant woman to evaluate vitamin D deficiency, since there is no sufficient evidence to recommend it. Nevertheless, in pregnant women considered at risk for vitamin D deficiency a periodic monitoring of serum 25 OH vitamin D3 should be taken into account and its interpretation should be based on the clinical status, the color of the skin and the seasonal variations.

Prevalence of Hypovitaminosis D

Hypovitaminosis D may be observed in all age groups. Reserves of vitamin D acquired by infants during pregnancy can already be over between the first and the second month of life as breast milk contains a small amount of vitamin D and many mothers become deficient if they do not take adequate supplements (1000 – 1500 UI per day). A review of studies carried out on healthy American children, even with great variability, has underlined the seriousness of the problem, especially for breast-fed infants without vitamin D supplementation, in which prevalence reaches 78%.

Considering a serum 25 OH vitamin D3 level of 30 ng/ml as sufficient, the National Health and Nutrition Examination Survey (NHANES III) has estimated that, in the U.S.A., 69% of pregnant women and 78% of not pregnant women between the age of 13 and 44 suffer from a deficiency of vitamin D. Moreover, the same survey has highlighted a general increase of hypovitaminosis in the American population over the last few years.

About one third of adolescents and young adults suffer from different degrees of hypovitaminosis D.

A recent cohort survey carried out on healthy Hungarian adults over the age of 50 reported a high prevalence of hypovitaminosis in more than 50% of the subjects, and also a correlation between hypovitaminosis and major osteoporotic fracture probability.

The elderly, especially if institutionalized, are more likely to suffer from vitamin D deficiency. In this age group the prevalence of hypovitaminosis can exceed 70% in springtime. A multicentric Italian study, carried out on healthy women between the age of 60 and 80 (who came to centers for osteoporosis diagnosis), has shown serum levels <12 ng/ml in 76 % of the subjects.

To reduce the size of the problem, the practice of adding vitamin D to food is spreading across some European countries and North America.

Skeletal effects of Hypovitaminosis D

Hypovitaminosis D may cause a serious and widespread demineralization of the bones and consequently bone frailty, defining a clinical picture of osteomalacia in adults, while in children cases of vitamin D deficiency rickets might be observed. These cases are characterized by ossification failure, growth reduction, deformities and skeletal frailties.

The effect of vitamin D supplementation over the fracture risk (mainly as cholecalciferol) has been researched in many surveys and meta-analysis. These cases have shown a significant reduction, while in others a significant statistic improvement has not been found. The disagreement among the results can be explained by the different levels of compliance among the studies, different patient criteria and also by the different ways of administration of vitamin D.

A recent meta-analysis, carried out on more than 30,000 subjects, which has taken into account the actual dose of vitamin D taken by patients and the serum levels of the hormone, reported that supplementation of vitamin D (≥ 792 UI/die) resulted in a significant reduction in the risk of fracture (hip fracture: 30% reduction; other non-vertebral fractures: 14 % reduction), while a reduced dose did not show a statistically relevant reduction. These results support the hypothesis of a dose-dependent effect of vitamin D in fracture risk.

The effectiveness of the hormone supplementation was observed in all the subjects over the age of 65 regardless of gender, age, basal levels of vitamin D in the serum and whether they lived in retirement homes or they were institutionalized.

It has been observed that the combined supplementation of vitamin D and calcium produces a further reduction of risk only if vitamin D levels are adequate and that such a reduction increases when the dose of calcium is above 1g/die. On the contrary, the only assumption of the calcium dose determined an increase in the risk of hip fracture.

Moreover, a correlation between very small levels of 25 OH vitamin D3 and a significant damage to everyday activities (Activities of Daily Living) and mobility (Mobility ADL) has been hypothesized – activities such as going out, climbing up the stairs, walking for at least 400 meters, carrying heavy objects.

As a whole, medical literature supports the recent recommendations of the Institute of Medicine, pointing out that a maximum benefit in the prevention of osteopathic fractures can be reached by maintaining serum levels of 25 OH vitamin D3 > 24 ng/ml.

Regarding fetal health, calcium demand mainly occurs in the third trimester of pregnancy, when skeleton mineralization begins. In this phase the placenta produces a greater amount of 1,25 (OH)2 vitamin D3 and of the related peptide parathyroid hormone (PTHrP). Consequently, in the mother, intestinal absorption of calcium and phosphate increases and PTH levels decrease so that she can preserve her skeleton integrity.

An association between hypovitaminosis D and muscle weakness was observed, leading to a higher risk of falls and fractures, especially femoral ones. As a matter of fact, several clinical trials carried out on elderly patients (both institutionalized and not) showed a significant reduction of fall risk after daily vitamin D supplementation of 700-1.000 IU/die.

Moreover, since the activation of VDRs promotes the correct cell differentiation, an adequate vitamin status should help to prevent breast, ovary colon and prostate cancer. However, from a clinical point of view a preventive effect of vitamin D on cancer risk has not yet been proved.

Vitamin D seems to have a protective effect on the neuronal system: its deficiency has been associated with a higher incidence of multiple sclerosis, Parkinson’s disease, schizophrenia and Alzheimer’s disease, while an adequate vitamin D status would improve mnemonic and learning skills, as well as motor control.

Vitamin D also plays a critical role in immune regulation, both innate and acquired, especially in skin, in the respiratory and digestive system through macrophage activity modulation and anti-microbial peptides production, by paracrine suppression of T-lymphocyte activation and lymphokine production.

An inverse correlation between the progression of the disease and 25 OH vitamin D3 levels has been observed in rheumatoid arthritis patients.

A random and monitored trial showed that the administration of vitamin D, in addition to pharmacological treatment, fasten the recovery of the patients affected by pulmonary TBC.

Some researchers highlighted a possible correlation between low levels of vitamin D and seasonal influenza, which notoriously reaches its peak between December and March, when vitamin levels in the blood decrease.

Hypovitaminosis D causes altered insulin synthesis and secretion, both in animals and human beings, and consequently a tendency to glucose intolerance and type 2 diabetes mellitus. This mechanism is regulated not only by hypercalcemia control but also by a direct action over pancreatic cell function. The prevalence of acute hypovitaminosis D (< 5 ng/ml) has also been confirmed in type 2 diabetic women compared with a sample group.

The data concerning the effects of hypovitaminosis D on cardiovascular diseases have interestingly revealed that vitamin D supplementation reduces the risk of ischemic heart disease, hypertension, heart failure and stroke.

Several studies have suggested that vitamin D deficiency may involve serious extraskeletal consequences before and during pregnancy, during the perinatal period and in infancy. A recent meta-analysis of observation studies found out how low serum levels may be associated with infertility, bacterial vaginosis, preeclampsia, gestational diabetes, preterm birth, Caesarean section and post-partum depression. However, further random studies are necessary to confirm these data.

Another recent study hypothesized an association between 25 OH vitamin D3 in maternal serum at the beginning of pregnancy and the quality of neuropsychological development of the infant.

Infants whose mothers had blood levels of 25 OH vitamin D3 > 30 ng/ml showed a better mental and psychomotor development (2.6 and 2.3 points) compared with infants whose mothers had levels of 25 OH vitamin D3 < 20 ng/ml. The effects of the optimal levels of 25 OH vitamin D3 should be attributed to neurotrophic and neuroprotective actions, which can potentially play a leading role in nervous tissue modification acting on gene expression in different cerebral areas.

Finally, recent studies suggest that vitamin D deficiency in pediatric age may be associated with infections, allergies and autoimmune diseases.

Requirement and supplementation of vitamin D

Since it is regarded as more effective than vitamin D2, vitamin D3 is currently used for supplementation in Italy and Europe instead of vitamin D2, more widespreadin the USA and in Anglo-Saxons countries.

Table 2 shows the recommendations of the American Institute of Medicine (IOM) and the American Endocrine Society concerning the adequate vitamin D supplementation for all age groups. Recommended daily doses vary from 600 to 2.000 UI/die. For pregnant women, the supplementation – necessary to reach the adequate level of 25 OH vitamin D3 in the serum – varies between 400 to 2.000 UI per day.

The 2012 study MAVIDOS, one of the first random double-blind tests, suggests that daily administration of 1000 UI to pregnant women with low levels of vitamin D (starting from the fourteenth week of pregnancy until childbirth) can improve bone mineral density in children. A recent clinical report by the Committee on Nutrition of the American Academy of Pediatrics (AAP) has suggested that a daily intake of 4.000 UI would be an adequate dose to reach the optimal level of 25 OH vitamin D3 (> 30 ng/ml), a definitely higher dose compared with the one recommended by the Food and Nutrition Board.

Even if there are few data to confirm the necessity of higher doses, most of the experts agree on the safety of vitamin D daily supplements of up to 4.000 UI during pregnancy and breastfeeding. It should be reminded that the multivitaminic potions used during pregnancy contain vitamin D doses of less than 400 UI.

Unfortunately, there are not many studies available about vitamin D supplementation during the breastfeeding period. A recent trial recommends a cholecalciferol daily intake of 1600 UI for the infant, underlining nevertheless the risk of hypercalcemia.

There isno substantial agreementon vitamin D dosage and duration of preventive healthcare during child development. The AAP does not set a limit to the duration of preventive healthcare but insists on an intake of 400 UI/die during the whole child development. In 2011, the IOM suggested a supplementation of 400 UI/die during the first year of life and 600 UI/die during the following years.

This kind of intervention in prenatal age and in the very first years of life could reduce the risk of autoimmune diseases and cancer, and also improve neupsychic development through a stable epigenetic effect, i.e. a persistent modification of some gene expression, determined by environmental factors, without modifying their structure.

Italian pediatricians essentially prescribe vitamin D supplementation throughout the first two years of life, with special attention to preterm infants. During this period, growth and bone mineral density processes are very active and the sun exposure of the child does not generally provide the adequate amount of vitamin D. Afterwards, in children and adolescents, vitamin D prescription should be tailored to sun exposure or possible risks.

For the elderly, a cholecalciferol supplementation of 800 UI/die is recommended, possibly associated with a calcium supplementation of 500-1000 mg/die, even without a preliminary control of 25 OH vitamin D3 serum levels, since cholecalciferol therapy has limited and easily controllable side effects.

Vitamin D requirements may vary according to comorbidities, such as precarious nutritional condition, intestinal malabsorption or concurrent therapies with anticonvulsants or glucocorticoids. In such cases, and in clinical cases of acute deficiency as well (25 OH vitamin D3 < 5 ng/ml), that is in cases of documented kidney or blood insufficiency, the administration of hydroxylated metabolites may be useful (25 OH vitamin D3 or 1,25 (OH)2 vitamin D3), only for the time it takes to restore a sufficient level of vitamin D3, since these metabolites are quickly available to the organism needs but increase the risk of hypercalcemia without close serum tests.

In hepatic and renal chronic diseases, vitamin D deficiency shows peculiar features as there is a failure in the enzymatic activities (25-hydroxylase hepatic and 1-alpha renal hydroxylation) necessary for calcifediol and calcitriol synthesis. This results in a parathyroid hormone overproduction which can be treated with cholecalciferol, calcifediol, calcitriol and its analogous (e.g. paricalcitol) and, in selected cases, with calcimimetics drugs (cinacalcet), which act on calcium cell receptors (used only for kidney diseases).

Among the different products available on the market, oral cholecalciferol is the most suitable for patients without severe kidney failure. The supplementation has proved to be effective even using different dosage schemes, from once a day to once a year, the overall amount being equal. In fact, vitamin D pharmacokinetics allows the supplementation in depot form (e.g. 25.000 UI orally once a month or 300.000 UI once a year by intramuscular injection or orally), with documented benefits concerning the prevention of femoral fractures.

Foods fortified with vitamin D are available in many countries. For instance, in the United States, milk and dairy products with the addition of vitamin D3 or D2 are common, while in other countries these molecules have been added to cereals and baked products. In Italy, some calcium and vitamin D supplements products have been put on the market only recently.

Vitamin D intoxication is very uncommon in patients treated with cholecalciferol and it represents a metabolic emergency, since it can provoke hypercalcemia, hypercalciuria, polyuria, polydipsia, confusion, nausea, asthenia and bone pain. However, this condition was documented only in subject given high daily doses for an extended period of time (Attachment 3).

Conclusions

A highprevalence of hypovitaminosis D was observed in all age groups. Medical literature data clearly show the general underestimate of this problem in clinical practice, whereas it should be given serious consideration, not only in order to prevent clear rickets cases (due to rare acute deficiencies) but most of all in order to guarantee a lifelong optimal vitamin status (25 OH vitamin D3 > 30 ng/ml).

Right from the first months of gestation, optimal vitamin D level in the serum may have a positive effect not only on the progress of pregnancy but also on the fetus, protecting the mental and psychomotor development of the infant.

In the elderly, a correct vitamin supplementation can help to prevent falls and fractures, improving muscular performance. Moreover, it may also protect against the onset of neoplasia and several common chronic and degenerative diseases.

Nowadays our relationship with sun exposure is quite contradictory. On the one hand we fear the damages from excessive sun exposure, on the other hand we are aware of the importance of UVB rays for the production of vitamin D and we are beginning to realize that some of our habits (artificial lightning at the workplace, air pollution exposure, more and more protective sun creams) are moving us far away from the only natural vitamin D source that has accompanied human evolution (Attachment 2).

SKIN AND SUN EXPOSURE

The radiations emitted by the sun reaching the earth’s surface are made up of 95% UVA rays and 5% UVB rays.

UVA rays are more active in promoting the production of melanin as a protective response to sun exposure, while UVB rays are 50 times much more active than UVA in stimulating skin 7 dehydrodholesterol to produce vitamin D, but, at the same time, they favour the onset of erythemas and cutaneous burns.

It is should be highlighted that overexposure to sunlight can cause skin injuries and annul the production of vitamin D.

Moreover, we should keep in mind that water, sand, snow and cement reflect up to 85% of sunlight and that UVRs penetrate into the water at a depth of 60 cm.

Guidelines to sun exposure

Infants:

Some studies report a high percentage of sunburns already in the first year of life, so before 6-12 months of age sun exposure must be very gradual and limited because the skin is thinner and the stratum corneum has not been developed yet.

Some experts recommend limiting summer sun exposure to the first hours of the day for 2-3 minutes, and only to face (with a hat on), forearms and legs for the first 2 days, until a slight erythema appears.

Photoprotectors should be avoided before 6 months of age because in this period a first gradual exposure to the sun is essential for stimulating the melanocytic endowment. High sun protection factor sunscreens can be used only on small areas of limb skin, if there are no shady areas, or it is better to wear suitable clothes. In fact, clothes can be an effective barrier to ultraviolet radiations, especially for children who spend several hours on the beach; dark or red clothes are better because, compared with white ones, they absorb more radiations.

Children:

The exposure to the maximum intensity of sunlight – from 10 of the morning to 16 in the afternoon – should be limited wearing suitable clothes, brimmed hats and sunglasses.

Pediatricians should provide patients with targeted advice in the spring and in the summer, especially in anticipation of the holidays at the seaside or in the mountains, as part of their health supervision activities for patients, encouraging them to do outdoor physical activities.

Adolescents and adults:

Adolescents are considered a high risk group for improper sun exposure, since it has been highlighted that, even after an educational campaign focused on this matter, they change their knowledge but not their behaviour.

From 12 a.m. to 16 p.m. sun exposure should be avoided or, at least, high sun protection factor sunsreeens are recommended.

Pediatricians are required to support information campaigns discouraging the access to tanning centers with artificial sources of UVR.

Elderly:

In the elderly, the same sun exposure produces an amount of vitamin D four times lower than in young people.

EPIGENETICS

GENETIC information sets the work plan through gene structure, that is the project for the construction of the proteins necessary for the optimal functioning of body cells, while EPIGENETICS, which is a branch of MOLECULAR BIOLOGY, provides the instructions to develop this project ensuring that proteins are correctly produced according to the time and manner required by the variable environmental conditions in which our organism find itself in the course of life.

While gene structure remains stable over time, except for rare mutation cases caused by errors in DNA transcription, the epigenetic information changes depending on our interactions with the environmental stimuli. Vitamin D in the serum has to reach a level >30 ng/ml so that calcitriol [1-25 (OH)2 vitamin D3], its active metabolite, could function as an hormone on vitamin D specific receptors, which can be found in the cell core and in most of the body tissues, and in order to have extraskeletal effects on the human body.

Calcitriol and the specific nuclear receptor (VDR) form a complex which act as a nuclear transcription factor on specific DNA segments regulating the expression of about 200 genes; the mechanism that determines which gene should produce a specific protein, and therefore which gene would “turn on”, is defined GENE REGULATION. Not all genes are turned on at the same time; their activity changes depending on life circumstances, the type of organ involved, climate, stress and diet. Environment does not only affect our habits but it may also modify the expression of our DNA without altering its structure. Errors in the silencing of some gene may alter the spatial organization of chromatin, which in turn may inhibit some genes that act as tumor suppressors or some others that are responsible for repairing altered DNA. In fact, these errors have been usually found in several types of tumors.

There are several types of gene expression regulation:

1) DNA METHYLATION, at the level of one of the nucleotide bases, mostly cytosine, which selectively inactivates the transcription process.

2) MODIFICATION OF CHROMATIN STRUCTURE due to HISTONES, proteins associated with chromosomes, which make the DNA more compact and therefore less accessible to the transcription apparatus (heterochromatin). Histones acetylation causes chromatin decondensation and thus promotes transcription, while methylation inhibits it.

3) EPIGENETIC RNA, different from the more known messenger RNA.

4) GENOMIC IMPRINTING: is an epigenetic regulation of the gene dosage, generally in the germline.

Foods rich in folate (vitamin B9), dietary methyl sources, are green leafy vegetables, beets, citrus fruits and strawberries. Another vitamin that can supply with methyl groups is vitamin B12, which can be found in fish, meat, milk and eggs.

Zhu and others analysed the methylation of leukocyte DNA among vitamin D deficient subjects (< 10 ng/ml) and African-American adolescents of the same age with vitamin D serum levels > 30 ng/ml. Some genes with very high levels of methylation were identified in vitamin D deficient subjects: DHCR7 (7-dehydrocholesterol reductase enzyme), CYP2R1 (25-hydroxylase hepatic microsomal enzyme) and CYP24A1 (24-hydroxylase enzyme), each of them involved in vitamin D metabolism. The DIO3 gene hypermethylation – a gene involved in thyroid metabolism – was observed in the group of vitamin D deficient patients. Hematologic cancers show a high level of methylation of this gene as well. What still needs to be clarified is whether the variations in methylation levels are the cause or the consequence of vitamin D deficiency.

Epigenetics, a great innovation in biology, can help us understand vitamin D extraskeletal effects through further high quality randomized controlled studies. This studies could be conducted following the pattern of FUNCTIONAL GENOMICS, which studies pathogenesis mechanisms using techniques to identify all the genetic material, proteins and metabolites that characterize a specific functional state of cells and tissues, both in the presence of a disease and in health. As for pregnancy, neonatology and pediatrics, we can say that “fetal programming” and the “developmental plasticity” are the two basic concepts of epigenetics. We need the metabolic details of how maternal vitamin D supplementation influence the metabolism and health of the fetus. DNA does not control genetic programming, but it contains a multitude of potential information originating from billions of years of molecular evolution, whereas the definitive genetic programming of each individual is built in the nine months of fetal ontogeny based on the information coming from the mother and the environment, because differentiating cells are extremely plastic and sensitive to the different epigenetic markings that define the basic programme of our phenotype construction.

TOXICITY OF VITAMIN D

It is widely known that drug therapies are not equally effective in patients with the same diagnosis. This individual variability is due to several factors including age, sex, body weight, diet, but, most of all, the genetic patrimony of each individual (pharmacogenetics).

Drug metabolism, and therefore also vitamin D metabolism, is controlled by about 60 genes which regulate the production of cytochrome P450 enzymes, mostly localised in the liver.

The enzyme involved in calcitriol synthesis is 1-alpha-hydroxylase, the cytochrome P450 27 B1 isozyme, while the one responsible for its catabolism is 24 hydroxylase, the cytochrome P450 24.Z isozyme.

These enzymes are present in most of our body tissues including the reproductive system and the immune system (lymphocytes, monocytes, macrophages). The calcitriol produced in this tissues is not usually released in blood circulation and is not regulated by blood levels of calcium, phosphorous and parathyroid hormone. This extra-renal synthesis of calcitriol is regulated by cytokines and it is important for paracrine regulation of cells differentiation and their function.

There are concerns about the possible toxic effects resulting from excessive vitamin D supplementation. A serum level of 25 OH D3 (calcifediol) above 150 ng/ml is defined as “intoxication”.

During pregnancy, the American Institute of Medicine (IOM) recommends a daily administration of 400-600 UI to reach a vitamin D serum level of 20 ng/ml as the optimal level to ensure skeletal health.

On the contrary, the American Society of Endocrinology recommends a daily intake of 1500-2000 UI to achieve a vitamin D3 circulating rate of >30 ng/ml.

The excessive caution of the IOM can be related to the second postwar British experience, when idiopathic infantile hypercalcemia was attributed to vitamin D supplementation to both children and pregnant women. However, vitamin D dosage in the serum was not yet available at that time and so it is not possible to know the amount of dose used or the blood level of the intoxicated subjects.

In 1966 vitamin D was viewed as the cause of SAS syndrome. Now, SAS is known as Williams syndrome, a genetic disorder due to the rupture of the elastin gene and the contiguous genes on chromosome 7g 11-23. The children affected by this disorder showed an excessive response to correct doses of vitamin D caused by an overproduction of calcitriol by macrophages.

Hypervitaminosis D causes an hypercalcaemic syndrome and represents a metabolic emergency. The toxic effects are more due to chronic supplementation than to a single very high dose.

We need to keep in mind that some patients with chronic granulomatous diseases – such as as sarcoidosis, chronic granulomatous disease, active tubercolosis, Williams syndrome and lymphoproliferative disorders – may develop a particular form of toxicity even for the administration of an adequate dose of vitamin D due to the concomitant production of calcitriol induced by macrophages.

In pediatric patients vitamin D intoxication is due not only to self-medication or excessive use of fortified food, but also to improper prescriptions, not always correctly put into writing and mostly misinterpreted by whom administers the drug.